2098 J , Org. Chem,, VoZ. $7,
No. IS, 1972
NEWKOME, ROACH, MONTELARO, AND HILL
Synthesis, Resolution, and Stereochemistry of
5-Hydroxy-10-alkyl-A1~g~-2-octalones’ GEORGE R. NEWKOME,*~ L. C. ROACH, AND R. C. MONTELARO Department of Chemistry, Louisiana State University, Baton Rouge, Louisiana 70803
R. K. HILL Department of Chemistry, University of Ueorgia, Athens, Georgia 30601 Received October 14, 1971 The 5-hydroxy-10-methyl- (ethyl- and isopropyl-) A1(g)-2-octalones(2) have been prepared and the corresponding phthalate half esters have been resolved by means of their brucine salts. From the ORD and CD data, (+)-5p-hydroxy-10p-alkyl-A1~g~-2-octalones and (- )-5a-hydroxy-l0a-~lkyl-A~~*~-2-octalones have been assigned the 55,105 and 5R, 10R configurations, respectively.
I n connection with a current project dealing with the synthesis of optically active cyclic olefins,lb it became necessary to synthesize, resolve, and determine the absolute configuration of the title compounds before proceeding with this project. Syntheses of chiral steroid synthetic intermediates, such as 1 and 2, have been accomplished by r e s o l ~ t i o n , ~microbiological -~ reductions,’ and most recently by “chiral induction.*” In view of the various diversified routes of resolution, it was deemed desirable to find a simple, suitable chemical resolution of 2 and to attempt their structural correlation via ORD and CD. The starting 2-methyL9 and 2-ethyl-10-1,3-cyclohexanediones were prepared by the previously outlined routes. The 2-isopropyl-1,3-cyclohexanedione was synthesized by an improved five-step sequence of Bhattacharyyall in an overall 30% yield (Scheme I). The application of this scheme for the synthesis of 2tert-butyl-1,3-cyclohexanedione was successful until the terminal cyclization stage. None of the desired product was isolated; the details of this reaction course will be published elsewhere. (1) (a) Part 1. Chiral Cyclic Olefins. (b) Presented in part at the Southwest Regional Meeting of the American Chemical Society, Tulsa, Okla., Dee 1969, ORGN 30; and 161st National Meeting of the American Chemical Society, Los Angeles, Calif., March 1971, ORGN 33. (2) T o whom correspondence should be addressed. (3) L. Velluz, G. Komin6, G. Amiard, V. Torelli, and J. CBr&de,C.R. Acad. sei,, a w , 3086 (1963). (4) Z. G. Hojos, D. R. Parrish, and E. P . Olivetd [Tetrahedron, 24, 2039 (1968) ] have recently resolved the related 7,7a-dihydro-l-hydroxy-7amethyl-5(6H)-indanone (i). (5) W.R . bdams, 0. L. Chapman, J. €3. Sieja, and W. J. Welstead, Jr., J . Amer. Chem. Soc., 82, 162 (1966), partially resolved 10-methyl-A1cQ)-2ootalone (ii) by fractional recrystallization of the d-camphor-10-sulfonic acid salt of the pyrrolidine enamine of ii.
i
ii
(a) Also see A . J. Speeiale, J. A . Stevens, and Q.E. Thompson, i b i d . , 76, 5011 (1954). (7) (a) V. Prelog and W. Acklin, Helu. Chim. Acta, 89, 748 (1956); (b) W.Acklin, V. Prelog, and D. Z#ch, i b i d . , 41, 1416, 1424, 1428 (1958); (0) V. Prelog, U.8. Patent2,833,694 (1959); Chem. Abstr., 58, 3179d (1959); (d) V. Prelog, Swiss Patent 366,530 (1964); Chem. Abstr., 80, 431c (1964); (e) H. H. Weston, Helu. Chim. Acta, 47, 575 (1964). (8) U. Eder, G. Sauer, and R . Weichert, A n g e ~Ckem., . Int. E d . En&, 10, 496 (1971). (9) (a) H. Schick, G. Lehmann, and G. Hilgetag, ibid., 6 , 80 (1967); (b) H. Schick and G. Lehmann, J . Pralct. Chem.. [41 38, 361 (1968); (0) 8.B. Mekler, S. Ramachanchan, 8. Swaninathan, and M.S. Newman, Org. Syn., 41, 56 (1961). (10) N. Stetter and W.Diericks, Ber., 85, 61 (1952). (11) P.C. Bhattacharyya, J . I n d i a n Chem. Soc., 42, 467 (1965).
0
0
CH,
The Robinson annelation sequence, that is, the Michael addition of methyl vinyl ketone to 2-methyl1,3-cyclohexanedione followed by dehydration, gave (50%) the known (&)-methyl bicyclic diketone la.12 An alternate route utilizing the intermediate pyrrolidine enamine was used for the synthesis of racemic lb and IC. This latter route seems to be preferable for the bulkier 2-alkyl substituted 1,3-cyclohexanediones in order to increase the activity of the carbonyl compound toward the initial R4ichael-type addition. The saturated carbonyl group la has been stereoselectively reduced with either sodium borohydride13 or lithium tri-tert-butoxyaluminum hydride t o afford the +unsaturated keto alcohol 2a (Scheme 11). Although 2a is an 0i1,14 both 2b and 2c are crystalline solids. The stereochemistry of the hydroxyl group in 2a has been adequately established, since the attacking hydride will approach the 1-keto group from the less hindered a side; therefore, the p-equatorial configuration of the hydroxyl function in 2b and 2c seems justifiable. The nmr spectra of 2 also showed a doublet of doublets (J = 7 and 7 He) for the >CHOH proton. These data correspond to the P-equatorial assignment of the hydroxyl group and are in rather good agreement with nmr data reported for steroids.16 The resolution of 2 can be accomplished by their initial conversion to the corresponding hydrogen phthalates by standard procedures, and then subsequent reso(12) (a) S. Swaminathan and M. S. Newman, O r g . Sun., 41, 38 (1961); (b) M. 8 . Newman and A. B. Mekler, J. Amer. Chem. Soc., 82, 4039 (1960); (0) 6. Swaminathan and M. S. Kewman, Tetrahedron, 2, 88 (1968); (d) P. Wieland and K. Miescher, HEZU.Chem. Acta, 88, 2215 (1950). (13) (a) C. B.C. Boyce and J. S. U‘hitehurst, J . Chem. Soc., 2680 (1960): (b) J. D. Cocker and T. G. Halsall, zbid., 3441 (1957). (14) The anhydrous oil solidified on exposure t o moisture: the hydrate can be recrystallized with difficulty from ether,’*@’mp 58-59’. (15) D . H. Williams and N. S. Bhacca, J . Amer. Chem. Soc., 86, 2742 (1964).
J . Org. Chem., Vol. 37, No. 13, 1972 2099 lution as a typical carboxylic acid.16 Although Pasteur's method of resolution is commonly employed, the use of chiral amines, e.g., (+)-1-phenylethylamine, (+)-1-(1-naphthyl)ethylamine, and dehydroabietyl amine,I7failed in our hands to afford separable diasteroisomeric salts. The sucCessfu1 resolution of 3 was accomplished with the use of brucine in acetone, or less preferably benzene. After several recrystallizations, nearly pure specimens of the diastereoisomeric salts of 3a can be achieved, although after one recrystallization ca. 50% optical purity is obtained. No attempts were made herein to prepare pure samples of these salts. Simple extraction of the alkaloid with cold dilute hydrochloric acid regenerated the chiral phthalate half esters (+)-or (-)-3.
Structural Correlations. -As alluded to earlier,'g the characteristic shapes of ORD, as well as CD, curve of a given a,@-unsaturatedketone should be governed predominantly by the unsaturated chromophore rather than by any additional substituents unless certain conformational factors interfere. Since the structure of (+)-2a appears t o be s u b ~ t a n t i a t e das~ ~ (58,108)-5~~~ hydroxy-10-methyl-A~~9~-2-octalone and the ORD curve measuredlZ0it could serve as an excellent standard for the assignment of the configurations of the angular alkyl function in 2b and 2c. 6
20
SCHEME I1
IO 8 1
6
2
4 0
C0,H
(\1
'0 x n
----t
43
U
0
--f
(+)-3, (-1-3
a, R
-*-4 -6 -8
-10
3
Brucine salt
2
0
3
-20
(+I -2 R
oH
CH,
b, R = CHSCH, C, R = (CHJZCH
The removal of the phthalate group is a facile process via treatment with dilute aqueous base. I t was found, however, that on prolonged contact with base the freed chiral 2 easily rearranged t o l-hydroxy-4-alkyl-5,6,7,8tetrahydronaphthalene, which is the product of a diene-phenol-type rearrangementala To avoid this unwanted side reaction, a heterogeneous mixture of dilute aqueous base containing 3 and ether was rapidly stirred at 0-10" with constant addition and removal of the product contained in the ether extract. After several minutes of such continuous extraction, the product was isolated in high yield and contaminated with little or no rearranged material.
(16) For a recent review concerning the methods of optical resolution, see P. H. Boyle. Quart.Rev., Chem. SOC.,26, 323 (1971). (17) W.J. Gottstein and L. C . Cheney, J . Org. Chem., 90, 2072 (1965), described the isolation of dehydroabietyl amine from Amine D, which was generously supplied by Hercules Powder Co. (18) J. B. Jones, J. D. Leman, and P. W . Marr, Can. J. Chem., 49, 1604 (1971), and references cited therein.
Figure 1.-Optical rotatory dispersion curves of 5-hydroxy-10alkyl-A1(a)-2-octalones(methanol).
I n Figures 1 and 2 are reproduced the ORD and CD curves, respectively, of (+)-2 and (-)-2. Since (+)2b and (+)-2c differ only in the size of the angular alkyl substituent, it is evident that except for some amplitude changes, the ORD and CD curves are nearly identical with those of (+)-2a, thus establishing the congeneric absolute configurations. Similarly, the dispersion curves of (-)-2 are of a mirror image relationship to that of (+)-2a and, therefore, possess the opposite configuration. From the ORD and CD curves, (+)-2 and (-)-2 are assigned the (58,lOX) and (5Rl10R) configurations, respectively.
(19) See (a) C. Djerassi, Bull. SOC.Chim. Fr.,7 4 1 (1957); (b) C . Djerassi, "Optical Rotatory Dispersion: Application to Organic Chemistry," MCGraw-Hill, New York, N. Y . , 1960, p 83; (c) P. Crabbe, "Optical Rotatory Dispersion and Circular Dichroism in Organic Chemistry," Holden-Day, San Francisco, Calif., 1965, p 191. (20) C . Djerassi, J. Osiecki, and W. Herz, J. Org. Chem., 82, 1361 (1957).
2100
J. Org. Chem., Vol. 37, N o . 13, 1972
NEWKOME, ROACH, MONTELARO, AND HILL
(*)-5-~ydroxy-10-ethyl-A1~e~-2-octalone (2b) was prepared (92%) by the ethanolic sodium borohydride reduction of the 20 diketone lb following the procedure of Boyce and Whitehurst:'S* bp 140-144' (0.05 mm); mp 87-88' [lit.zabp 165' (0.8 mm); mp 88.0-89.5'1; ir (neat) 1670 (C=O), 1625 (C=C), and 3450 em-1 (OH); nmr (CC1d 6 0.96 (CH3CHn-, t , J = 7 Hz, 3 H), 3.7 (CHaCHz-, q, J = 7 Hz, 2 H), 5.99 (-CH=CCHO, dd, J = 6, 6 Hz, 1 H), 5.88 (HC=CCHO, dd, J = 7 , 7 Hz, 1 H ) , 6.00 (HC=C
